CENTER FOR DRUG EVALUATION AND RESEARCH€¦ · Ankur Kalola, PharmD Regulatory Review Officer : Office of Prescription Drug Promotion (OPDP) Subject: Review of Patient Labeling:

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

761156Orig1s000

OTHER REVIEW(S)

Department of Health and Human Services Public Health Service

Food and Drug Administration Center for Drug Evaluation and Research

Office of Medical Policy

PATIENT LABELING REVIEW

Date: August 17, 2020

To: Linda V. Galgay, RN, MSN Senior Regulatory Project Manager Division of General Endocrinology (DGE)

Through: LaShawn Griffiths, MSHS-PH, BSN, RN Associate Director for Patient Labeling Division of Medical Policy Programs (DMPP) Sharon Williams, MSN, BSN, RN Senior Patient Labeling Reviewer Division of Medical Policy Programs (DMPP)

From: Nyedra W. Booker, PharmD, MPH Patient Labeling Reviewer Division of Medical Policy Programs (DMPP) Ankur Kalola, PharmD Regulatory Review Officer Office of Prescription Drug Promotion (OPDP)

Subject: Review of Patient Labeling: Patient Package Insert (PPI) and Instructions for Use (IFU)

Drug Name (established name):

SOGROYA (somapacitan-xxxx)

Dosage Form and Route:

injection, for subcutaneous use

Application Type/Number:

BLA 761156

Applicant: Novo Nordisk Inc.

Reference ID: 4657546

1 INTRODUCTION On August 28, 2019 Novo Nordisk Inc. submitted for the Agency’s review an Original Biologics License Application (BLA) 761156 for SOGROYA (somapacitan-xxxx) injection, for subcutaneous use. The proposed indication for SOGROYA (somapacitan-xxxx) injection, for subcutaneous use is for the replacement of endogenous growth hormone (GH) in adults with growth hormone deficiency. This collaborative review is written by the Division of Medical Policy Programs (DMPP) and the Office of Prescription Drug Promotion (OPDP) in response to a request by the Division of General Endocrinology (DGE) on September 8, 2019 for DMPP and OPDP to review the Applicant’s proposed Patient Package Insert (PPI) and Instructions for Use (IFU) for SOGROYA (somapacitan-xxxx) injection, for subcutaneous use.

2 MATERIAL REVIEWED

• Draft SOGROYA (somapacitan-xxxx) for injection, for subcutaneous use PPI and IFU received on August 28, 2019 and received by DMPP and OPDP on August 6, 2020.

• Draft SOGROYA (somapacitan-xxxx) for injection, for subcutaneous use Prescribing Information (PI) received on August 28, 2019, revised by the Review Division throughout the review cycle, and received by DMPP and OPDP on August 6, 2020.

3 REVIEW METHODS To enhance patient comprehension, materials should be written at a 6th to 8th grade reading level and have a reading ease score of at least 60%. A reading ease score of 60% corresponds to an 8th grade reading level. Additionally, in 2008 the American Society of Consultant Pharmacists Foundation (ASCP) in collaboration with the American Foundation for the Blind (AFB) published Guidelines for Prescription Labeling and Consumer Medication Information for People with Vision Loss. The ASCP and AFB recommended using fonts such as Verdana, Arial or APHont to make medical information more accessible for patients with vision loss. We have reformatted IFU to Arial font, size 11. In our collaborative review of the PPI and IFU we have:

• simplified wording and clarified concepts where possible

• ensured that the PPI and IFU are consistent with the Prescribing Information (PI)

• removed unnecessary or redundant information

• ensured that the PPI and IFU are free of promotional language or suggested revisions to ensure that it is free of promotional language

• ensured that the PPI and IFU meet the criteria as specified in FDA’s Guidance for Useful Written Consumer Medication Information (published July 2006)


4 CONCLUSIONS The PPI and IFU are acceptable with our recommended changes.

5 RECOMMENDATIONS

• Please send these comments to the Applicant and copy DMPP and OPDP on the correspondence.

• Our collaborative review of the PPI and IFU is appended to this memorandum. Consult DMPP and OPDP regarding any additional revisions made to the PI to determine if corresponding revisions need to be made to the PPI and IFU.

Please let us know if you have any questions.

25 Page(s) of Draft Labeling have been Withheld in Full as B4 (CCI/TS) immediately following this page


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Signature Page 1 of 1

This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.

/s/

NYEDRA W BOOKER 08/17/2020 01:08:34 PM

ANKUR S KALOLA 08/17/2020 01:18:09 PM

SHARON W WILLIAMS 08/17/2020 01:20:01 PM

LASHAWN M GRIFFITHS 08/17/2020 01:45:37 PM


MEMORANDUM REVIEW OF REVISED LABEL AND LABELING

Division of Medication Error Prevention and Analysis (DMEPA) Office of Medication Error Prevention and Risk Management (OMEPRM)

Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER)

Date of This Memorandum: August 6, 2020

Requesting Office or Division: Division of General Endocrinology (DGE)

Application Type and Number: BLA 761156

Product Name and Strength: Sogroya (somapacitan-beco) injection, 10 mg/1.5 mL (6.7 mg/mL)

Applicant/Sponsor Name: Novo Nordisk, Inc

OSE RCM #: 2019-1822-1

DMEPA Safety Evaluator: Melina Fanari, R.Ph.

DMEPA Team Leader: Sevan Kolejian, PharmD, MBA, BCPPS

1 PURPOSE OF MEMORANDUM The Applicant submitted revised container labels and carton labeling received on July 23, 2020 for Sogroya. The Division of General Endocrinology requested that we review the revised container labels and carton labeling for Sogroya (Appendix A) to determine if they are acceptable from a medication error perspective. The revisions are in response to recommendations that we made during a previous label and labeling reviewa and by the Office of Biotechnology Productsb.

2 CONCLUSION The revised carton and container labels are acceptable from a medication error perspective and we have no additional recommendations at this time.

a Fanari, M. Label and Labeling Review for Sogroya (BLA 761156). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2020 Feb 11. RCM No.: 2015-1822. b Galgay, L Labeling PMR/PMC Discussion Comments for BLA 761156 Message to Nina Liang. Silver Spring (MD): FDA, CDER, OND, DGE (US); 2020 May 18

1


APPENDIX A. IMAGES OF LABEL AND LABELING RECEIVED ON JULY 23, 2020 available in EDR \\CDSESUB1\evsprod\BLA761156\0053\m1\us

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/s/

MELINA N FANARI 08/06/2020 09:30:35 AM

SEVAN H KOLEJIAN 08/06/2020 10:54:28 AM


FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and ResearchOffice of Prescription Drug Promotion

****Pre-decisional Agency Information****

Memorandum Date: July 28, 2020

To: Geanina Roman-Popoveniuc, M.D., Medical Officer Division of Metabolism and Endocrinology Products (DMEP)

Linda Galgay, Project Manager, (DMEP)

Monika Houstoun, Associate Director for Labeling, (DMEP)

From: Charuni Shah, Regulatory Review Officer Office of Prescription Drug Promotion (OPDP)

Through: Melinda McLawhorn, Team Leader, OPDP

Subject: OPDP Labeling Comments for SOGROYA® (somapacitan) injection, for subcutaneous use

BLA: 761156

In response to DMEP’s consult request dated September 8, 2019, OPDP has reviewed the proposed product labeling (PI), Instructions for Use (IFU), and Patient Package Insert (PPI) for SOGROYA® (somapacitan) injection, for subcutaneous use. This is a New Drug Application.

PI, IFU, PPI: OPDP’s comments on the proposed PI are based on the draft materials sent by DMEP on July 23, 2020 and are provided below.

Please note that comments on the PPI and IFU will be provided under separate cover as a collaborative review between OPDP and the Division of Medical Policy Program (DMPP).

Thank you for your consult. If you have any questions, please contact Charuni Shah at (240) 402-4997 or [email protected].

15 Page(s) of Draft Labeling have been Withheld in Full as B4 (CCI/TS) immediately following this page


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/s/

CHARUNI P SHAH 07/28/2020 02:36:55 PM


DEPARTMENT OF HEALTH & HUMAN SERVICES

Food and Drug Administration Silver Spring, MD 20993

ME MO R A ND U M DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH

TO: BLA 761156

FROM: Gettie Audain, Senior Regulatory Health Project Manager Division of Pediatric and Maternal Health (DPMH)

SUBJECT: Division of Gastroenterology (DG) consult to DPMH (DARRTS Reference ID 4488423) requesting pediatric-related input and meeting attendance

DRUG: Sogroya (somapacitan) injection

DG submitted a consult request to DPMH dated September 8, 2019 requesting pediatric-related input and meeting attendance to participate in internal discussions on several internal meetings, Sponsor meeting with a focus on ClinPharm and CDRH comments on February 13, 2020, and the PeRC meeting on May 12, 2020.

The DPMH-Pediatric Team reviewed the Sponsor’s meeting package’s and attended all internal DG meeting discussion from October 2019 to June 2020 along with support at the February 13, 2020 Sponsor meeting.

No further action is required from DPMH. This consult is considered closed.

DPMH Pediatric MO Reviewer – Ndidi Nwokorie DPMH Medical Team Lead – Mona Khurana DPMH RPM – Gettie Audain DPMH RPM Team Lead – George Greeley


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/s/

GETTIE AUDAIN 06/18/2020 09:56:47 AM


BLA 761156, ICC1900756 Sogroya (NNC0195-0092) [long-acting growth hormone] – Somapacitan; Novo Nordisk

Date 5/14/2020 To: Linda Galgay (CDER/OND/ODEII/DMEP) Requesting Center/Office: CDER/OND Clinical Review Division: DMEP From Matthew Ondeck

OPEQ/OHT3/DHT3C Through (Team) Rumi Young, Team Lead, Injection Team

OPEQ/OHT3/DHT3C Through (Division) *Optional

CPT Alan Stevens, Assistant Director OPEQ/OHT3/DHT3C

Subject BLA 761156, Sogroya (NNC0195-0092) [long-acting growth hormone] – Sompacitan ICC1900756 Case 00011422 & 00012868

Recommendation The Device Constituent Parts of the Combination Product are Approvable

A post-approval inspection is required for:

Firm Name: Novo Nordisk A/S Address: Kirke Værløsevej 30, DK-3500 Værløse, Denmark FEI #: 3015545250

The inspection recommendation was sent to Lindsey Schwierjohann (FDA/ORA) on October 25, 2019 by email.

Digital Signature Concurrence Table Reviewer Team Lead (TL) Division (*Optional)

Matthew Ondeck -S

Digitally signed by Matthew Ondeck -S Date: 2020.05.14 10:23:18 -04'00'

Rumi Young -S

Rumi Young -S c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, cn=Rumi Young -S, 0.9.2342.19200300.100.1.1=2002467913 2020.05.22 10:34:31 -04'00'

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1. SUBMISSION OVERVIEW

Submission Information Submission Number BLA 761156 Sponsor Novo Nordisk Drug/Biologic Sogroya (NNC0195-0092) [long-acting growth hormone]

Indications for Use Replacement of endogenous Growth Hormone (GH) in Adults with growth hormone deficiency (GHD)

Device Constituent Pen-Injector Related Files N/A

Review Team Lead Reviewer/Engineering Matthew Ondeck (CDRH\OHT3\DHT3C) Biocompatibility Consultant Gang Peng (CDRH\OHT3\DHT3C)

Important Dates Interim Milestones Due Date Meeting Date Filing 10/27/2019 10/17/2019 74-Day Letter 11/8/2019 N/A Midcycle (Internal) N/A 1/27/2020 Midcycle (External) N/A 2/13/2020 Final Device Consult 4/28/2020 N/A Late cycle (External) N/A 4/29/2020 Wrap Up (Internal) N/A 6/29/2020 Goal Date 8/28/2020 N/A

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TABLE OF CONTENTS

1. SUBMISSION OVERVIEW........................................................................................................................... 2 TABLE OF CONTENTS........................................................................................................................................ 3 2. PURPOSE/BACKGROUND .......................................................................................................................... 5

2.1. Scope ........................................................................................................................................................ 5 2.2. Prior Interactions ...................................................................................................................................... 5 2.3. Indications for Use ................................................................................................................................... 5 2.4. Materials Reviewed.................................................................................................................................. 5

3. DEVICE DESCRIPTION................................................................................................................................ 6 3.1. Device Description................................................................................................................................... 6 3.2. Steps for Using the Device..................................................................................................................... 14 3.3. Device Description Conclusion.............................................................................................................. 14

4 .............................................................................. 14 .............................................................................. 14 .............................................................................. 18 .............................................................................. 21 .............................................................................. 21

5. LABELING ................................................................................................................................................... 22 5.1. General Labeling Review....................................................................................................................... 22 5.2. Instructions for Use Review................................................................................................................... 22 5.3. Labeling Review Conclusion ................................................................................................................. 27

6. DESIGN CONTROL SUMMARY............................................................................................................... 27 6.1. Summary of Design Control Activities.................................................................................................. 27 6.2. ..................................................................................................................... 28 6.3. Applicable Standards and Guidance Documents ................................................................................... 36 6.4. Design Control Review Conclusion....................................................................................................... 36

7. RISK ANALYSIS ...................................................................................... 36 7.1. ...................................................................................... 36 7.2. ...................................................................................... 38 7.3. ....................................................................................... 40

8. DESIGN VERIFICATION REVIEW........................................................................................................... 41 ............... 41 ............... 41 ............... 44 ............... 44 ............... 49 ............... 55 ............... 58 ............... 65 ............... 67 ............... 84 ............... 85

8.4. Design Verification Review Conclusion................................................................................................ 88 9. CLINICAL VALIDATION REVIEW .......................................................................................................... 88

9.1. Clinical Validation Review Conclusion................................................................................................. 88 10. HUMAN FACTORS VALIDATION REVIEW....................................................................................... 88

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10.1. Human Factors Review Conclusion ................................................................................................... 90 11. FACILITIES & QUALITY SYSTEMS .................................................................................................... 91

11.1. Facility Inspection Report Review ..................................................................................................... 91 11.2. Quality Systems Documentation Review........................................................................................... 91

11.2.1. Description of the Device Manufacturing Process...................................................................... 91 11.2.2. cGMP Review ............................................................................................................................. 94 11.2.3. Corrective and Preventive Action Review (CAPA).................................................................... 96

11.3. Facilities & Quality Systems Review Conclusion.............................................................................. 96 12 ......................... 98

......................... 98

....................... 111

....................... 120

....................... 135

....................... 139 13. APPENDIX B (CONSULTANT MEMOS) ............................................................................................ 152

13.1. Biocompatibility Review Memo – Gang Peng................................................................................. 152

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2. PURPOSE/BACKGROUND2.1.Scope Novo Nordisk is requesting approval of Sogroya (NNC0195-0092) under a BLA submission. The device constituent ofthe combination product is a Pen-Injector.

CDER OND has requested a premarket device review of the device constituent and a quality systems review of the device manufacturing procedures. The review of the device will encompass all disciplines, except for human factors, as per an Intercenter MOU, CDRH does not review the human factors information for typical, non-emergency use pen injectors such as this under an CDER submission.

This review will provide an approvability recommendation, but the original review division will be responsible for the decision regarding the overall safety and effectiveness for approvability of the combination product.

2.2.Prior InteractionsN/A

2.3.Indications for UseCombination Product Indications for Use

Sogroya (NNC0195-0092) Replacement of endogenous Growth Hormone (GH) in Adults with growth hormone deficiency (GHD)

Pen-Injector Delivery of the Drug Product

2.4.Materials Reviewed Materials Reviewed Document Name Locationcover Seq0001.1container-closure-system-overview-device Seq0001.3.2.P.7container-closure-system-device Seq0001.3.2.P.7draft-ifu Seq0001.1container-closure-system-perf-safety Seq0001.3.2.P.7specifications Seq0001.3.2.P.5.1container-closure-system-summary Seq0001.3.2.P.7

container-closure-system-bio-eval Seq0001.3.2.P.7

container-closure-system-shelf-life Seq0001.3.2.P.7

re-fda-ir-20191104 Seq0011.121cfr-part-820-info-devices Seq0001.3.2.P.3.3

manuf-process-and-controls- Seq0001.3.2.P.3.3manuf-process-and-controls Seq0001.3.2.P.3.3container-closure-system-test Seq0011.3.2.P.7Summary of Human Factors Validation Seq0001.5.3.5.4resp-ir-20200210 Seq0025.1resp-ir-20200305 Seq0030.1resp-ir-20200324 Seq0031.1resp-ir-20200424 Seq0042.1

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3. DEVICE DESCRIPTION 3.1.Device DescriptionThe sponsor provides a device description in document: container-closure-system-device. The information below is taken from this document:

The somapacitan 10 mg pen-injector is a drug-device combination product containing a 1.5 ml cartridge with the drug product somapacitan at a concentration of 10 mg/1.5 ml (Figure 1). The device is intended for once weekly subcutaneous injection of somapacitan

Reviewer Note:The product is labeled to have a 24 month shelf life at 2-8 °C including an in-use period of 6 weeks at 2-8 °Cincluding 72 hours (3 days) at or below 30 °C.

The drug product is enclosed within the cartridge and not in contact with the device. The device is intended to connect to a standard needle thread or a needle with a bayonet coupling prior to drug product administration. Labelling is not shown in the figure.

From the perspective of technical performance, the somapacitan 10 mg pen-injector was developed to fulfil the international standard for drug injectors, ISO 11608-1:2014 (Needle-ba ction systems for medical use -requirements and test methods - Part 1: Needle-based injection systems) [1].

The dimensions of the device are shown in Figure 2.

A technical explanation for how these features are built into the design is presented in section 3.

The somapacitan 10 mg pen-injector consists of 17 components and a 1.5 ml cartridge. A compatible needle is not part of the pen-injector, but is needed in order to make an injection

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The components are made from the following

The 1.5 ml cartridge is made

All of the component materials are identical to existing marketed devices, such as the Norditropin® FlexPro®. All materials that form the user interface have been evaluated for biocompatibility and do not pose a risk of cytotoxicity, skin irritation and skin sensitisation, or any other biological hazard as defined in ISO 10993-1:2018 [2] when used as intended.

Reviewer Note:The sponsor has confirmed that they “only design differences between the Norditropin® FlexPro® (1.5 ml) and the to-be-marketed somapacitan 10 mg pen-injector are the colors of the cap, cartridge holder and dose button.”The sponsor should state that the patient contacting materials are identical to the marketed devices. They will need right of reference to be able to state this. The components that are drug contacting are deferred to CDER.

Update 1/22/2020:The firm has provided additional biocompatibility information in Seq0011.1, doc: re-fda-ir-20191104. This is being reviewed with Section 8.3 of the memo by biocompatibility reviewer Gang Peng.

Technical Description:The principle of operation of the somapacitan 10 mg pen-injector can be described as two interacting systems: a dial system and a dose system.

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Reviewer Notes – 2/27/2020A discussion with Injection TL Rumi Young was held on 2/27/2020. See the notes below:

The pen does not have any audible feedback when the injection is complete, only when the injection button is activated. There is visual feedback; i.e. the dial reaching 0, but the user must wait 6 seconds after the dial reaches 0 and the visual feedback that the pen has can be covered up by the user’s hand the way it is designed if held inappropriately. In addition, the device is designed in such a way that if the user were to let go of the dosing button midway through the delivery (prior to the dial reaching zero) the full dose would not be delivered. To address the likelihood of this, the human factors study will be analyzed to address whether users could adequately administer the full dose. Of note, the identical pen design (aside from colorants) and mechanism is used in the Norditropin® FlexPro® pen. See Section 10. In addition the sponsor provided the verification to demonstrate adequate risk mitigation.

Update 5/5/2020 –The sponsor addressed the risk of underdose if the user was to not hold the device for 6 seconds after the dose dial reaches 0 during injection. The data that was provided to demonstrates adequate risk mitigation was that the user will receive ~ % of the intended dose even at the smallest Gauge needles (30-32 G), if they were to remove the needle once the dial reaches 0, and not hold the dose button down for the labeled 6 seconds. This risk is acceptable, given that there were very few users who did not follow this instruction as a part of the human factors study with Norditropin. See Section 7.2 – Risk Summary Report Review, where this was reviewed more fully.

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The device is a different design then a typical pen injector;

Update 3/24/2020 –The sponsor has provided an explanation regarding how to achieve a full dose

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Reviewer Note – 3/3/2020:Given that the user is not fully in control of the system, injection time; i.e. time after dial goes to 0, that the full dose is delivered, should be a essential performance requirement. See Section 8.1.

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Reviewer Note: Based on the prescribing information, the doses that can be delivered are:

Initiate TRADE NAME with a dose of approximately 1.5 mg/week for treatment naïve patients or for patients switching from daily growth hormone (somatropin). Increase the dose every 2-4 weeks by increments ofapproximately +0.5 mg to +1.5 mg, based on the clinical response and serum insulin-like growth factor 1 (IGF-1) concentrations. Maintenance dose should not exceed 8 mg/week

The sponsor should clarify how they will control for last dose accuracy

Update 10/28/2019:In document container-closure-system-test, it is stated that the product contains a controls

.

The somapacitan 10 mg pen-injector complies with this general design requirement As explained in 3.2.P.7 Somapacitan

pen-injector – Device Description, this is a design feature

The sponsor lists the following summary testing:

The design mitigation appears appropriate; however, the summary testing does not adequately verify i.e. the acceptance criteria makes no sense. The sponsor should

provide testing/test results that demonstrate that .

Update 1/22/2020:The firm provided a response to an IR requesting this verification testing. They state that during dose testing, that the operator confirms the effect

. This is adequate.

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3.2. Steps for Using the DeviceSee Section 5.2, where the instructions for use are reviewed. This analyzes the use steps associated with the device.

3.3. Device Description Conclusion

DEVICE DESCRIPTION REVIEW CONCLUSIONReviewer Recommendation:The device description is adequate.

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5. LABELING5.1. General Labeling ReviewThe labeling, including the device constituent labeling, user guides, patient information, prescriber information and all other labeling materials provided for review were reviewed to meet the following general labeling guidelines as appropriate:

General Labeling Review ChecklistAdequate

Yes No NotesIndications for Use or Intended Use; including use environment(s); route(s) of administration for infusion, and treatment population.

X N/A

Drug name is visible on device constituent and packaging X N/ADevice/Combination Product Name and labeling is consistent with the type of device constituent

X N/A

Prescriptive Statement/Symbol on device constituent X Prescribing Info

Warnings X N/AContraindications X N/AInstructions for Use X – See below N/A

5.2. Instructions for Use ReviewThe steps for using the device was taken from the device IFU:

4 Pages of Draft Labeling have been Withheld in Full as B4(CCI/TS) Immediately Following this Page

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Reviewer Comments Based on my review of the use steps they appear appropriate for a user to properly use the device. The instructions for use will be validated through human factors testing; however this is beyond the scope of this review and is CDER/OSE/DMEPA’s responsibility. A cursory CDRH human factors review was conducted for performance design validation purposes. See Section 10.

5.3. Labeling Review Conclusion

LABELING REVIEW CONCLUSIONReviewer RecommendationThe device labeling is adequate. CDRH is NOT requesting labeling changes.

6. DESIGN CONTROL SUMMARY6.1. Summary of Design Control Activities

Risk Analysis Attributes Yes No CommentsRisk analysis conducted on the combination product X A risk analysis (dFMEA) was conducted by the firm. Hazards adequately identified (e.g. FMEA, FTA, post-market data, etc.) X Full dFMEA not provided; however summary risk

analysis information was provided. See Section 7. Mitigations are adequate to reduce risk to health X Full dFMEA not provided; however summary risk

analysis information was provided. See Section 7. Version history demonstrates risk management throughout design / development activities

X Full dFMEA not provided; however summary risk analysis information was provided. See Section 7.

Design Inputs/Outputs Yes No CommentsDesign requirements / specifications document present (essential performance requirements included)

X Sponsor provided traceability to requested design requirements and essential performance requirements in response to CDRH IRs.

Design Verification / Validation Attributes Yes No CommentsValidation of essential requirements covered by clinical and human factors testing

X Human factors testing was conducted and was examined in a cursory review. See Section 10. The full human factors review is conducted by CDER/OSE/DMEPA.

To-be-marketed device was used in the pivotal clinical trial X In response to an IR, the firm states:The clinical version of the device that is used for pivotal clinical trials has different colours for the cap,

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cartridge holder and dose button compared to the to-be-marketed pen-injector. These differences do not impact the performance of the pen-injector and therefore the devices are considered to be clinically equivalent.

This is adequate.Verification methods relevant to specific use conditions as described in design documents and labeling

X See design verification review section 8

Device reliability is acceptable to support the indications for use (i.e. emergency use combination product may require separate reliability study)

X See design verification review section 8

Traceability demonstrated for specifications to performance data X Sponsor provided traceability to requested design requirements and essential performance requirements in response to CDRH IRs.

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6.3. Applicable Standards and Guidance Documents Generally Applicable Standards and Guidance Documents:

Standard or Guidance Conformance/CommentsAAMI / ANSI / ISO 14971:2007/(R)2010 (Corrected 4 October 2007), medical devices - applications of risk management to medical devices

The sponsor states that: “All identified hazards and hazardous situations of the somapacitan pen-injectors have gonethrough a risk management process in line with ISO 14971.” Conformance to this standard is not mandatory; therefore the risk analysis will be analyzed in the risk analysis review section.

ISO 11608 - Needle-based injection systems for medical use -Requirements and test methods - Part 1: Needle-based injection systems

Sponsor conducts dose accuracy testing in accordance with this standard.

ISO 11608 - Needle-based injection systems for medical use -Requirements and test methods - Part 2: Needles

For needle compatibility – the submission states: “Dose accuracy at a high and low dose setting,according to ISO 11608-2”

ISTA 3A 2008 - Packaged-Products for Parcel Delivery System Shipment 70 kg (150 lb) or Less

The firm states: “The transport simulation testing is based on the ISTA 3A standard, which is an FDA-recognized consensus standard (recognition number 5-110).”

Use of International Standard ISO 10993-1, Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process"

The firm utilizes ISO 10993-1 to confirm biocompatibility.

6.4.Design Control Review Conclusion

DESIGN CONTROL REVIEW CONCLUSIONReviewer Recommendation:The design control information is adequate.

7. RISK ANALYSIS

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7.3.Risk Analysis Review Conclusion

RISK ANALYSIS REVIEW CONCLUSIONReviewer Recommendation The risk analysis is adequate

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8. DESIGN VERIFICATION REVIEW The following review disciplines are needed to review the submission. Note that no additional CDRH consults were obtained.

Discipline Review Needed (Yes/No/N/A) NotesEngineering (Materials, Mechanical, General)

Yes Reviewed by the lead reviewer. See Section 8.1-2

Biocompatibility Yes Reviewed by the consulting reviewer, Gang Peng. See Section 8.3Sterility N/A The device is not provided sterileSoftware / Cybersecurity N/A The device has no electrically active components. Electrical Safety / EMC N/A The device has no electrically active components.Human Factors N/A Given that this device is a pen injector the Intercenter policy is that

CDER/OSE/DMEPA will review the adequacy of the human factors information as a whole; however, design validation of design requirements that will utilize usability requirements; i.e injection force specification, will be reviewed. See Section 8.1

Clinical N/A It is the responsibility of the CDER clinical team to evaluate the clinical information associated with this product; however, clinical validation of the device is reviewed in Section 9 of the review memo.

Quality Systems/Facilities Yes Reviewed by the lead reviewer in Section 11

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8.4.Design Verification Review Conclusion

DESIGN VERIFICATION REVIEW CONCLUSIONReviewer Recommendations:The design verification information is acceptable

9. CLINICAL VALIDATION REVIEWThere are no specific clinical studies for CDRH to review. This is the responsibility of the CDER clinical team. This section of the review will address clinical validation of the device design.

In Seq0011.1, doc: re-fda-ir-20191104, in response to IR#1, comment #8, the firm states that there are differences between the clinical version of the device that was used in pivotal clinical studies and the to-be-marketed version. These differences as listed by the firm are the following: The clinical version of the device that is used for pivotal clinical trials has different colours for the cap, cartridge holder and dose button compared to the to-be-marketed pen-injector. These differences do not impact the performance of the pen-injector and therefore the devices are considered to be clinically equivalent.

Reviewer Note:I agree with the firm that these differences between the clinical use device and to-be-marketed device do not result in any functional changes or any changes that would affect the EPRs of the device.

The firm has provided an overview of the clinical studies that the clinical use device was used in:

Given the similarity in device design between the clinical use device and the to-be-marketed device, I believe that the device design is clinically validated.

9.1. Clinical Validation Review Conclusion

CLINICAL VALIDATION REVIEW CONCLUSIONReviewer Recommendation The device design has been adequately validated clinically.

10. HUMAN FACTORS VALIDATION REVIEWGiven that the device is a non-emergency use pen-injector, the adequacy of the human factors testing is deferred to CDER/OSE/DMEPA. Of note, the human factors study is provided in Seq0001.5.3.5.4. ut112, doc: val-device-use-ut112.

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In this report the firm used the Norditropin® FlexPro® 30 mg/3 mL peninjector was used for the human factors validation study rather than the somapacitan 10 mg pen injector. The Norditropin product is also a human growth hormone product; therefore, with similar intended users. I ultimately defer the adequacy of the product intended users to CDER/OSE/DMEPA. The sponsor has confirmed that they “only design differences between the Norditropin® FlexPro® (1.5 ml) and the to-be-marketed somapacitan 10 mg pen-injector are the colors of the cap, cartridge holder and dose button.” In addition, in response to a CDRH deficiency, the sponsor provides viscosity data of somapacitan to Norditropin to demonstrate that the viscosities are nearly equivalent and multiple temperature (See midcycle deficiencies); therefore, I believe that the firm can use the Norditropin product to support the usability of the device design. The firm will still need to demonstrate through human factors validation that their usability related specifications are adequately validated; i.e. activation force, injection (in terms of tolerability), etc.

Reviewer Note – 3/31/2020:The firm has an injection time specification at μL with an upper limit of seconds; the firm has only provided verification of lots of somapacitan and Norditropin pen injectors with a max injection time of seconds; this is well below seconds; if the firm intends to keep this specification at seconds they need to demonstrate through usability that it is adequately validated. See comment to Sponsor

Update 5/5/2020 –The firm updated their injection time specification . This was made based on their device validation and what their device was capable of achieving. The Sponsor provided an approximation of the injection time . This is acceptable.

Of note there was one use error related to underdose. The user was an HCP nurse and was the only error that would have resulted in underdose out of 94 total users in the study. The error occurred because the user released the dose button before the dial reached 0. See below:

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Reviewer Note:Given the design, which is described in the device description,

, which is somewhat different from a typical pen injector , it is possible that the design contributed to the error which I described

above; however, given that only one user (an untrained nurse) out of 94 users exhibited an issue with the injection; this is not an issue an issue of the device design.

Update 3/31/2020 –In response to an IR regarding this, the firm has stated that there was “first test scenario” and that “the same untrained HCP nurse had performed the previous injection in the first test scenario correctly”

10.1. Human Factors Review Conclusion

CLINICAL VALIDATION REVIEW CONCLUSIONReviewer Recommendation The human factors validation is deferred to CDER/OSE/DMEPA; however CDRH does not have any human factors or usability concerns with the device constituent.

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11.FACILITIES & QUALITY SYSTEMS 11.1. Facility Inspection Report ReviewA facilities inspection report will not be reviewed under the scope of this review memo, as a device pre-approval inspection was not conducted for this BLA. The manufacturing firm is provided below:

Firm Name: Novo Nordisk A/SAddress: Kirke Værløsevej 30

DK-3500 VærløseDenmark

FEI: 3015545250Responsibilities: Assembly, labelling and secondary packaging of finished drug product

Quality control of pen-injectors (dose accuracy)Storage of printed packaging materials, finished drug product

As stated in Section 4.2 of the current memo:

Based on a review of OSAR using the FEI#, the particular firm responsible for device assembly/manufacturing has never been inspected. The drug is not an emergency use product, the device is a typical pen injector, and it does not include vulnerable populations. Given this information, I believe that an inspection is necessary, however, given the risk of the product/users and lack of complexity of the device manufacturing processes, I believe that an inspection can be handledpost-approval.

Therefore, a post approval inspection was recommended.

Facilities Review Conclusion The Sponsor provided adequate information about the facilities

11.2. Quality Systems Documentation ReviewA CDRH QS review was conducted. See the review below:

11.2.1. Description of the Device Manufacturing Process

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Device Manufacturing Process ConclusionThe Sponsor has provided adequate information for the summary of the manufacturing process / production flow.

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11.2.2. cGMP ReviewThe sponsor has chosen a Drug cGMP QS approach. They have stated in Seq0001.3.2.P.3.3, doc: manuf-process-and-controls- : Novo Nordisk A/S is accountable for the finalcombination product somapacitan pen-injector; therefore, this information will be reviewed for this facility below. The information in the summary table below is taken from doc: manuf-process-and-controls-

According to the FDA Guidance: Current Good Manufacturing Practice Requirements for Combination Products (https://www.fda.gov/media/90425/download), the following are parts of 21 CFR 820 that require a firm to address:

21 CFR 820.20 Management responsibility21 CFR 820.30 Design controls21 CFR 820.50 Purchasing controls 21 CFR 820.100 Corrective and preventive action21 CFR 820.170 Installation 21 CFR 820.200 Servicing

21 CFR 820.20 Summary of Management Responsibility

Firm(s):Novo Nordisk A/S

Reviewer Discussion –The organizational structure is provided below:

They state:According to the Novo Nordisk A/S Quality Manual (see Table 1) the Head of Quality is theappointed management representative with executive responsibility. The Head of Quality hasresponsibility for all quality units, the maintenance and continuous improvement of the QualityManagement System and for reporting on the performance of the Quality Management System toexecutive management.

The Quality Manual describes that the GMP requirements for devices must be followed when Novo Nordisk develops and manufactures medical devices. This is also applicable for the device part of the combination products. The management representative within the quality unit of eachorganisational area has authority and responsibility for processes within their organisational area. They report to the Head of Quality. Quality Management reviews are conducted within all areas.

I believe that this summary is adequate.

21 CFR 820.30 Summary of Design Controls


Reviewer Discussion – Reviewed in detail in Section 7

A summary is provided by the firm:

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The information provided within the review represents that the firm is approaching design controls appropriately.

21 CFR 820.50 Summary of Purchasing Controls


Reviewer Discussion –The purchasing controls are described by the firm:

The firm describes control based on supplier/component risk, auditing, change control. The summary appears adequate.

21 CFR 820.100 Summary of


Reviewer Discussion –Reviewed in Section 12.2.3.

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Corrective and Preventive Actions21 CFR 820.170 Summary of Installation

N/A N/A

21 CFR 820.200 Summary Servicing

N/A N/A

GMP Compliance Summary Conclusion The Sponsor has provided adequate summary information about the GMP compliance activities

11.2.3. Corrective and Preventive Action Review (CAPA)The firm provides a description of their CAPA procedure in Seq0001.3.2.P.3.3, doc: 21cfr-part-820-info-devices.

The following table reflects whether the Sponsor addressed the required elements of corrective and preventive action controls in their description of CAPA activities. :

CAPA Procedure Required Elements PresentProcedures include requirements to analyze processes, work operations, concessions, quality audit reports, quality records, service records, complaints, returned product, and other sources of quality data to identify existing and potential causes of nonconforming product, or other quality problems.

Yes

Procedures include review and disposition process of nonconforming product, including documentation of disposition. Documentation shall include the justification for use of nonconforming product and the signature of the individual(s) authorizing the use.

Yes

Procedures include appropriate statistical analysis of these quality data to detect recurring quality problems YesInvestigations into the cause of nonconformities relating to product, processes, and the quality system YesIncludes requirements for identification and implementation of actions needed to correct and prevent recurrence of nonconformities and other quality problems

Yes

Verification or validation of the corrective and preventive actions taken to ensure that such action iseffective and does not adversely affect the finished device

Yes

Each manufacturer shall establish and maintain procedures for rework, to include retesting and reevaluation of the nonconforming product after rework, to ensure that the product meets its current approved specifications

Yes

Describes requirements for implementing and recording changes in methods and procedures needed to correct and prevent identified quality problems

Yes

Ensures that information related to quality problems or nonconforming product is disseminated to those directly responsible for assuring the quality of such product or the prevention of such problemsRequires documentation of all CAPA activities Yes

Reviewer Note:It appears that all relevant requirements of CAPA are included in their CAPA procedures.

CAPA Conclusion The Sponsor has provided adequate information for corrective and preventive actions.

11.3. Facilities & Quality Systems Review Conclusion

FACILITIES & QUALITY SYSTEMS REVIEW CONCLUSIONReviewer Recommendation:The QS/Manufcturing information is adequate.

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The Facilities information is adequate. A post approval inspection is recommended for the following firm:

Firm Name: Novo Nordisk A/SAddress: Kirke Værløsevej 30, DK-3500 Værløse, DenmarkFEI #: 3015545250

The inspection recommendation was sent to Lindsey Schwierjohann (FDA/ORA) on October 25, 2019 by email.

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13.APPENDIX B (CONSULTANT MEMOS)

13.1. Biocompatibility Review Memo – Gang PengA biocompatibility review was obtained DHT3C. The review memo from biocompatibility reviewer, Gang Peng, is below:

Memorandum: Biocompatibility Consult

To: Matt Ondeck, Lead Reviewer, GHDB/DAGRID/ODE/CDRHFrom: Gang Peng, Biomedical Engineer, GHDB/DAGRID/ODE/CDRH Date: February 19, 2020Subject: BLA 761156/CON 201725Device: pen-injector

Sponsor: Novo NordiskRecommendation: No further communication needed.

_________________________________________________________________________________Of note: quotes from the Sponsor are written in italics, comments to be directed to the Sponsor are in bold.

I. Scope of Consult RequestLead reviewer requested feedback on if biocomp is necessary as the firm cites identical materials except for colorant

II. Documents reviewedContainer closureBiocompatibility

III. BackgroundNA

IV. Indications for Use From IFU form:The somapacitan 10 mg pen-injector is a drug-device combination product containing a1.5 ml cartridge with the drug product somapacitan at a concentration of 10 mg/1.5 ml.The device is intended for once weekly subcutaneous injection of somapacitan.

V. Device DescriptionThe following device description was provided in the container closure document:

The somapacitan 10 mg pen-injector is a drug-device combination product containing a1.5 ml cartridge with the drug product somapacitan at a concentration of 10 mg/1.5 ml (Figure 1).

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The device is intended for once weekly subcutaneous injection of somapacitan.Figure 1 Somapacitan 10 mg in a 1.5 ml cartridge assembled in a pen-injectorThe drug product is enclosed within the cartridge and not in contact with the device. The device isintended to connect to a standard needle thread or a needle with a bayonet coupling prior to drugproduct administration. Labelling is not shown in the figure.

VI. Biocompatibility Summary

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Per the firm in the container closure biocompatibility document:The somapacitan 10 mg pen-injector is a drug/device combination product intended forsubcutaneous administration of somapacitan.The intended use of the somapacitan 10 mg pen-injector implies brief repeated contactwith intact skin during handling of the device. In accordance with ISO 10993-1:2018, thesomapacitan 10 mg pen-injector is categorised as a surface-contacting device (contact tointact skin) in Category B - Prolonged exposure (> 24 h and < 30 days). Based on this, thefollowing biological endpoints shall, as a minimum, be addressed in the biological evaluation of thedevices:

CytotoxicitySensitisationIrritation or intracutaneous reactivity

The components in the somapacitan 10 mg pen-injector which come in contact with theuser when handling the device are the Housing, Cap, Cartridge holder, Dial and Dose button. TheHousing, Cap, Cartridge holder and Dial component consist of identical materials compared to thecorresponding components of the currently marketed Norditropin® FlexPro® and other pen-injectors with the exception of the colour in the Cartridge holder and Cap.Furthermore, these components are manufactured by similar manufacturing processes as thecorresponding components of the currently marketed Norditropin® FlexPro® and other pen-injectors. Also the nature and duration of user contact to these components are similar to thecurrently marketed Norditropin® FlexPro® and other pen-injectors. Therefore, withreference to ISO 10993-1:2018, the Housing, Cap, Cartridge holder and Dial are considered to havean established history of safe use in the intended application.

Type/duration of contactContact type: Intact skin

Contact Duration: Prolonged (>24hr to 30 days)

Reviewer CommentsAgreed, this device should be considered prolonged skin contact

Per ISO 10993 guidance – attachment A:

A device with prolonged skin contact requires: Cytotoxicity Sensitization Irritation or Intracutaneous reactivity

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Reviewer CommentsIt is important to note that the biocompatibility primary container closure of the drug product, the cartridge, shall be CDER’s responsibility. As such, this biocompatibility review memo will focus on components which are not part of the primary container closure. The firm has stated that “The Housing, Cap, Cartridge holder and Dial component consist of identical materials compared to the corresponding components of the currently marketed Norditropin® FlexPro® and other pen-injectors with the exception of the colour in the Cartridge holder and Cap.” Per CDRH biocompatibility guidance, the biocompatibility evaluation shall be performed on the final finished device. As such, any changes in the device can be cause for additional testing. However, the firm has stated that the only difference lies within the colorant of the cap and cartridge holder, which would only have skin contact. Although colorants can present a biocompatibility concern, the following should be considered:1) The device is skin contacting. It is unlikely that colorants would pose a concern due to the

nature of patient contact. The firm has also provided a evaluation on the irriation and sensitization potential of the product through a toxicological data search on the

2) The firm performed a chemical analysis with 50/50 water ethanol, saline, and artificial sweat to show no new/high quantity of leachables in the new colorants.

Based on the above support, mainly due to the contact classification of the device, the change in colorant is acceptable and poses negligible biocompatibility risk. No further biocompatibility evaluation is necessary.

VII. RecommendationNo further communication needed.

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1

DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service

Division of Pediatric and Maternal Health

Center for Drug Evaluation and Research

Food and Drug Administration Silver Spring, MD 20993

Tel 301-796-2200 FAX 301-796-9744

Division of Pediatric and Maternal Health Review

Date: April 17, 2020 Date Consulted: September 8, 2019 From: Jeanine Best, MSN, RN, PNP, Senior Clinical Analyst, Maternal Health

Division of Pediatric and Maternal Health

Through: Tamara Johnson, MD, MS, Team Leader, Maternal Health Division of Pediatric and Maternal Health

Lynne P. Yao, MD, Division Director Division of Pediatric and Maternal Health

To: Division of Metabolism and Endocrinology Products (DMEP) Drug: Sogroya (somapacitan-xxxx) injection, for subcutaneous use BLA: 761156 Applicant: Novo Nordisk, Inc. Subject: Pregnancy and Lactation Labeling Indication: “for the replacement of endogenous GH in adults with growth hormone

deficiency (GHD)” Materials Reviewed:

• Applicant’s proposed labeling and Summary of Clinical Safety, 8/28/2019 • Applicant’s 120-Day Clinical Safety Update, 12/9/2019 • DPMH PLLR Review for Norditropin (somatropin), NDA /S037 and 038, by

Catherine Roca, MD, 2/7/2018, DARRTS Reference ID 42175781 1 This review was part of the materials reviewed but was not a source relied upon for labeling recommendations provided in this review for BLA 761156; furthermore, the applicant cross-referenced NDA in their BLA 761156 submission; the applicant owns both products.


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Consult Question: Provide a PLLR labeling review. INTRODUCTION AND BACKGROUND On August 28, 2019, Novo Nordisk, Inc. submitted an original BLA for Sogroya (somapacitan-xxxx) injection, for subcutaneous use, for the replacement of endogenous GH in adults with growth hormone deficiency (GHD). The Division of Metabolism and Endocrinology Products (DMEP) consulted the Division of Pediatric and Maternal Health (DPMH) on September 8, 2019, to assist with the Pregnancy and Lactation subsections of labeling. Regulatory History

• 7/23/2014 – IND 116327 submitted for NNC0195-0092 Long-Acting Human Growth Hormone (hGH) solution for injection, also known as somapacitan, for the proposed indication of replacement of endogenous growth hormone (GH) in adults with growth hormone deficiency (AGHD)

• 12/12/2014 - Waiver for 2-year rodent carcinogenicity issued (due to extensive clinical

experience with hGH and a lack of a carcinogenicity risk associated with hGH treatment). • 4/25/2019 – Pre-BLA Meeting. •

Somapacitan Drug Characteristics2

• A long-acting recombinant growth hormone (rhGH) derivative with a single substitution in the amino acid backbone to which an albumin binding moiety (side-chain) has been attached. The side-chain consists of an albumin binder and a hydrophilic spacer attached to position 101 of the protein (191 amino acids). Reversible binding to endogenous albumin delays elimination of somapacitan and prolongs the in vivo half-life and duration of action.

o Endogenous human growth hormone (hGH), somatotropin, is a 191-amino acid, single-chain polypeptide that is synthesized, stored and secreted by somatotropic cells within the pituitary gland. HGH is a mitogen which is specific only to the receptors on certain types of cells that stimulate growth, cell reproduction, and cell regeneration, thus, it is important in human development. HGH also stimulates production of insulin-like growth factor-1 (IGF-1) and increases the concentration of glucose and free fatty acids.3

o (Short-acting) recombinant human growth hormone (rhGH), somatropin, is a protein that is manufactured to be nearly identical to the main form of the naturally occurring hGH, somatotropin.4

• Molecular Weight: 23305.10 g/mol, of which the albumin binding moiety is 1191.39 g/mol.

• Mechanism of Action: Either directly via the GH-receptor and/or indirectly via insulin-like growth factor 1 (IGF-1) produced in body tissues, but mainly by the liver (IGF-1 is a

2 Refer to applicant proposed labeling, 8/28/2019 3 https://en.wikipedia.org/wiki/Growth hormone 4 https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/somatropin-information


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surrogate marker for the efficacy of growth hormone products). Major effects are on body composition (i.e., decreased body fat mass, increased body lean mass, increased bone mineral density) and metabolic action.

• Extensively plasma protein bound (>99%) and is expected to be distributed like albumin. • Half-life: 2 to 3 days • Metabolized via proteolytic cleavage of the linker sequence between the peptide

backbone and the albumin binder side-chain. • Primary routes of excretion are via urine (~81%) and feces (~13%). No intact

somapacitan is excreted which indicates full breakdown of product prior to excretion. • Exposure of somapacitan-xxxx decreases with increasing body weight; females,

especially females on oral estrogen, have lower exposure than males at same dose. • Not mutagenic or clastogenic; carcinogenicity studies were waived • Serious adverse reactions include: increased mortality in patients with acute critical

illness; increased risk of neoplasms (malignancy progression in patients with active malignancy); glucose intolerance and diabetes mellitus, intracranial hypertension; severe hypersensitivity, fluid retention, hypoadrenalism, hypothyroidism, pancreatitis, lypohypertrophy (at frequently used injection sites).

• Immunogenicity potential (therapeutic protein); no anti-somapacitan-xxxx antibodies detected in patients in the Phase 3 clinical trials in adult patients with growth hormone deficiency.

Proposed Sogroya PLLR Labeling5

• No Boxed Warning or Warning and Precaution for embryofetal toxicity; • No pregnancy or lactation contraindication; • No human pregnancy or lactation data; • Nonclinical pregnancy data: no embryofetal toxicity; • Nonclinical lactation data; drug present in rat milk at levels lower than plasma; • Drug interaction with oral estrogens: oral estrogens may reduce the serum IGF-1

response to Sogroya; patients on oral estrogens may require a higher dose of Sogroya (consistent with all rhGH product labeling.

REVIEW Pregnancy Adult Growth Hormone Deficiency Growth hormone deficiency is a rare disorder in both children and adults and is classified as genetic, idiopathic, or acquired. Adult growth hormone deficiency represents two distinct clinical situations; 1) patients diagnosed during childhood with growth hormone deficiency (GHD), typically due to a genetic or idiopathic cause, that continues into adulthood (15-20% of adult cases); and, 2) growth hormone deficiency acquired during adulthood, generally due to pituitary tumors or extra-pituitary tumors, and the treatment of such tumors, or head trauma. Approximately 6,000 adults per year are diagnosed with acquired GHD in the U.S. (~1/100,000 persons annually). There is no published data regarding the incidence of pregnancy in patients

5 Refer to applicant proposed labeling, 8/28/2019


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with GHD. Diagnosis typically occurs between the fourth and fifth decade of life.6 The clinical manifestations of adult-onset GHD include a change in body composition (decrease in lean body mass, increase in fat mass (both subcutaneous and visceral) which is greater in women, and a reduction in extracellular water and plasma volume; reduced bone mineral content and density, cardiovascular effects (decrease in ventricular mass, thickness of the interventricular septum, and ejection fraction); changes in cardiovascular risk parameters (characteristics of metabolic syndrome, including insulin resistance and adverse effects on lipid profile), neuropsychiatric and cognitive effects (depression, anxiety, memory processing effects fatigue); and increased mortality. Patients that were diagnosed during childhood (reported incidence 1/4000 to 1/10,000/year)7 tend to have manifestations that are more severe in adulthood than patients diagnosed with GHD as adults. Typical treatment consists of the use of somatropin (recombinant human growth hormone (rhGH)), with the goal of finding a dose that maintains serum insulin-like growth factor type 1 (IGF-1) within the middle of the age-adjusted normal range.8,9,10 There are no published treatment guidelines for treatment of women with GHD during pregnancy. Nonclinical Experience11 In animal reproduction studies, somapacitan was not teratogenic in rats and rabbits when administered subcutaneously during organogenesis at doses approximately 12-times the clinical exposure at the maximum recommended human dose (MRHD) of 8 mg/week. No adverse developmental outcomes were observed in offspring of rats administered somapacitan during organogenesis through lactation at approximately 275 times the clinical exposure at the MRHD. Clinical Experience Sogroya (somapacitan-xxxx) injection, for subcutaneous use has only been used in the applicant’s clinical trials and is not currently approved in any country. The applicant provided an Overview of pregnancy cases from ongoing and completed trials in their BLA submission and reports that no pregnancy cases were found. There is no published information on the use of Sogroya (somapacitan-xxxx) in pregnant women. Published Data with Growth Hormone Replacement Therapy in Pregnant Women **Disclaimer** Pregnancy-related literature relied upon for this review and pregnancy and lactation labeling recommendations is not specific to a particular drug or biological product.

6 https://emedicine medscape.com/article/120767-overview#a6 7 https://www.uptodate.com/contents/diagnosis-of-growth-hormone-deficiency-in-children, accessed 2/5/2020 8 Alexopoulou O, Abs R, Maiter D. Treatment of adult growth hormone deficiency: who, why, and how” a review. Acta Clinica Belgica, 2014; 65(1):13-2 9 https://www.ncbi nln.nih.gov/pmc/articles/PMC3183535/ 10 https://www.uptodate.com/contents/growth-hormone-deficiency-in-adults?search=adult%20growth%20hormone%20deficiency&source=search result&selectedTitle=1~125&usage type=default&display rank=1; accessed 1/29/2020 11 Refer to the final Nonclinical Review, 4/17/2020


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Several authors have tried to determine the use, benefit, and safety of GH replacement therapy in pregnant women with GHD.

Vila, et al. (2015)12 analyzed pregnancies reported in KIMS, the Pfizer International Metabolic Database of adult patients with GHD treated with growth hormone replacement therapy. KIMS was a large, prospective, pharmacoepidemiology study of hypopituitary adults with GHD from 800 outpatient centers in 31 countries performed between 1994 to 2012. Enrollment was 16,442 patients which included 8,290 males and 8,152 females (5,092 females between 16 to 50 years of age). The authors identified 201 pregnancies (173 in female patients; 28 in female partners of male patients). Pregnancy outcomes were available for 19/28 pregnancies in female partners of male patients; 1 spontaneous abortion, 21 live births (1 twin birth and 1 triplet birth); and no malformations were reported. The following outcomes were reported for the 173 pregnancies in female patients exposed to growth hormone replacement therapy (outcomes known in 139 pregnancies, unknown in 34 pregnancies). Growth hormone replacement therapy use and dose before conception and during pregnancy was prescribed per local clinic practice with use known in 170/173 pregnancies (81/170 pregnancies stopped GH therapy at beginning of pregnancy; 42/170 pregnancies continued GH replacement therapy to 2nd or 3rd trimester; and 47/170 pregnancies continued GH replacement therapy throughout pregnancy).

• Elective termination – 4/139 • Spontaneous abortion – 26/139 • Stillbirth – 1/139 • Malformation – 1/139 (severe cystic hygroma; patient terminated the pregnancy) • Live births – 107/139 (118 babies including twin and triplet births) • Preterm births – 12/139 (5 at 37 weeks gestation – 2/5 in twin pregnancies; 5 at 32-24

weeks gestation – 1/5 in twin pregnancy; 2 at 28-29 weeks gestation – 1/2 in twin pregnancy; 1/2 in triplet pregnancy

Maternal complications were available in 67 pregnancies with live birth outcomes:

• Gestational diabetes – 10% of pregnancies • Pre-eclampsia - 6% of pregnancies • Pregnancy-associated hypertension – 4% of pregnancies • Vaginal bleeding – 5% of pregnancies • Unspecified complications – 13% of pregnancies

The authors found no relationships between pregnancy outcomes, complications, gestational week at delivery, or infant birthweight and age, BMI, etiology and extent of GHD, comorbidities before pregnancy, conception method, IGF-1 levels before pregnancy, or GH replacement dose at the time of pregnancy, or extent of GH replacement therapy use during pregnancy. Furthermore, the authors state that the placenta, which acts as an endocrine organ, secretes a GH variant called placental growth hormone (PGH). PGH continually increases during pregnancy,

12 Vila G, Akerblad AC, et al. Pregnancy outcomes in women with growth hormone deficiency. Fertility and Sterility, 2015; 104(5):1210-1217


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peaking at 35 to 36 weeks gestation. PGH has a high affinity for GH receptors, gradually replacing pituitary GH and controlling production of maternal IGF-1. Giampietro, et al (2009)13 described four women with GHD who began treatment with rhGH replacement therapy due to infertility. All women spontaneously achieved pregnancy after treatment with GH replacement therapy and therapy was discontinued in all women upon diagnosis of pregnancy. All women had full term, healthy infants. Muller, et al. (1995)14 described the case of a 25 year old woman who was diagnosed with idiopathic isolated GHD at age 7 years of age, began treatment with GH replacement therapy at some point and continued receiving the therapy during pregnancy until there was evidence of sufficient PGH production. Serum GH and IGF-1 levels increased during the second half of pregnancy. Serum IGF binding protein 3 (IGFBP-3) remained normal throughput pregnancy. The pregnancy resulted in a full-term, healthy infant with a birthweight of 3.6 kg. Maternal serum levels of GH fell within 1 hour of delivery and IGF-1 and IGFBP-3 decreased into the range of GHD within 4 days. The authors concluded that the role of GH replacement therapy during pregnancy in women with GHD should be studied further. Curran, et al. (1998)15 conducted a retrospective record review of 77 women with known GHD. Twenty five pregnancies were identified in women with GHD without GH replacement therapy. There were 26 live births which included 1 set of twins and 1 set of quadruplets (8 pregnancies were achieved with ovulation induction), 4 spontaneous 1st trimester abortions, and 3 minor congenital abnormalities. Gestation ranged from 33 to 42 weeks (median 39 weeks). There were 2 cases of preeclampsia and 1 case of postpartum hemorrhage. Median birth weight, uncorrected for gestational age, and excluding multiple births, was 3.09 kg (range 1.64 kg to 4.19 kg). The authors concluded that the lack of GH replacement therapy in pregnant women with GHD did not adversely affect maternal or fetal outcomes and that GH replacement therapy is probably not essential for GH-deficient females during pregnancy. Wiren, et al. (2002)16 studied the safety of a GH replacement therapy dosing regimen in 12 pregnancies in women with GHD. GH replacement therapy was maintained at pre-pregnancy doses during the 1st trimester, gradually decreased during the 2nd trimester, and discontinued during the 3rd trimester. All pregnancies resulted in successful outcomes. The median gestation time was 40 weeks (range 33 to 42 weeks) and no congenital malformations were reported. The authors concluded that this GH replacement regimen for pregnant women with GHD was safe as there were no side effects reported and no negative adverse maternal or fetal outcomes were observed.

13 Giampietro A, Milardi D. The effect of treatment with growth hormone on fertility outcome in eugonadal women with growth hormone deficiency: report of four cases and review of the literature. Fertility and Sterility, 2009; 91(3):7-11 14 Muller J, Starup J, et al. Growth hormone treatment during pregnancy in a growth hormone deficient woman. Eur J Endocrinol, 1995; 132:727-729 15 Curran AJ, Peacy SR, et al. Is maternal growth hormone essential for a normal pregnancy? Eur J Endocrinol, 1998; 139:54-58 16 Wiren I, Bogusczewski CL, et al. Growth hormone (Gh) replacement therapy in GH-deficient women during pregnancy. Clin Endocrinol, 2002; 57:235-239


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Lenburg, et al. (2003)17 assayed placental growth hormone (PGH) levels in maternal circulation throughout pregnancy in 17 normal women and in one growth hormone-deficient woman who received GH replacement therapy throughout pregnancy. The authors found that levels of placental growth hormone in maternal circulation increase throughout pregnancy from as early as 8 weeks of pregnancy, with maximum levels found around week 35 of gestation. The pregnancy-induced rise in placental growth hormone levels in the growth hormone-deficient patient was comparable to the rise seen during normal pregnancies and was not suppressed by the concurrent human growth hormone treatment. REPROTOX18 reports that available data with the use of rhGH (somatropin) have not described adverse effects on pregnancy outcomes. Lactation Nonclinical Experience19 In a pre- and post-natal study in rats, somapacitan was found to be secreted in rat milk up to 50% of drug plasma levels. No adverse developmental effects were observed in pups with maternal doses resulting in an exposure of greater than 600 times the expected maximum clinical exposure. Clinical Experience Sogroya (somapacitan-xxxx) injection, for subcutaneous use has only been used in the applicant’s clinical trials and is not currently approved in any country. The applicant provided a summary of use of somapacitan in lactation in their BLA submission and reports that no lactation cases were found. There is no published information on the use of Sogroya (somapacitan-xxxx) in lactating women. Growth Hormone and Lactation **Disclaimer** Lactation-related literature relied upon for this review and pregnancy and lactation labeling recommendations is not specific to a particular drug or biological product.

17 Lenburg U, Damm P, et al. Increase in maternal placental growth hormone during pregnancy and disappearance during parturition in normal and growth-hormone deficient pregnancies. Am J Obstet and Gynecol, 2003; 188:247-251 18https://www micromedexsolutions.com/micromedex2/librarian/CS/86930C/ND_PR/evidencexpert/ND_P/evidencexpert/DUPLICATIONSHIELDSYNC/E58275/ND_PG/evidencexpert/ND_B/evidencexpert/ND_AppProduct/evidencexpert/ND_T/evidencexpert/PFActionId/evidencexpert.IntermediateToDocumentLink?docId=3635&contentSetId, =35&title=GROWTH HORMONE&servicesTitle=GROWTH HORMONE&navResults=clinicalRefTox, accessed 1/30/2020 19 Refer to the final Nonclinical Review, 4/17/2020


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The use of recombinant growth hormone (rhGH), somatropin, during lactation is described in REPROTOX,20 LactMed,21 and Hale’s Medications & Mother’s Milk.22

• REPROTOX describes data that show effectiveness of somatropin in increasing milk production in both normal lactating women and in women with lactation insufficiency.

• LactMed reports that limited data from studies examining the effect of somatropin on milk production in normal lactating women and those with lactation insufficiency indicate that 7 days of exogenous somatropin does not increase normal breastmilk concentrations of growth hormone and no adverse effects are experienced in breastfed infants. In one study, 8 lactating women were administered 0.1 IU/kg/day of somatropin (within the labeled dosage recommendations of somatropin for GHD) for 7 days. There was no difference in human growth hormone concentrations in breastmilk before Day 1 and after 7 days of rhGH administration; however, there was an increase in milk concentration of insulin-like growth factor-1 (IGF-1) over the same time period.23 In addition, no adverse effects were reported in breastfed infants from this study and none were reported from two other studies (n=34 total infants) investigating the use of somatropin as a galactagogue; however, all studies involved only 7 days of short-acting rhGH administration.24,25,26 Although, an increase in milk production was observed with somatropin administration to both normal lactating women and those with lactation insufficiency; the data were not deemed sufficient to support the efficacy of somatropin as a galactagogue and larger studies would be needed.27

• Hale’s Medications & Mother’s Milk reports on the same studies discussed by LactMed. Hale also reports that due to the long peptide chain and large molecular weight, somatropin is unlikely to transfer into breastmilk, and if it were present, oral absorption by a breastfed infant would be nil.28

20https://www micromedexsolutions.com/micromedex2/librarian/CS/86930C/ND_PR/evidencexpert/ND_P/evidencexpert/DUPLICATIONSHIELDSYNC/E58275/ND_PG/evidencexpert/ND_B/evidencexpert/ND_AppProduct/evidencexpert/ND_T/evidencexpert/PFActionId/evidencexpert.IntermediateToDocumentLink?docId=3635&contentSetId=35&title=GROWTH HORMONE&servicesTitle=GROWTH HORMONE&navResults=clinicalRefTox, accessed 1/30/2020 21 https://www.ncbi.nlm.nih.gov/books/NBK501496/, accessed 1/30/2020 22 https://www.halesmeds.com/monographs/61420?q=somatro, accessed 1/30/2020 23 Breier BH, Milsom SR, et al. Insulin-like growth factors and their binding proteins in plasma and milk after growth hormone-stimulated galactopoiesis in normally lactating women. Acta Endocrinol, 1993;129:427-435 24 Milsom SR, Breier BH, et al. Growth hormone stimulates galactopoieisis in healthy lactating women. Acta Endocrinol, 1992; 127:337-343 25 Mislom sR, Rabone DL, et al. Potential role for growth hormone in human lactation insufficiency. Horm Res, 1998; 50:147-150 26 Gunn AJ, GunnTR, et al. Growth hormone increases breastmilk volumes in mothers of preterm infants. Pediatrics; 1996; 98(2 pt1):279-282 27 Mislom SR, Rabone DL, et al. Potential role for growth hormone in human lactation insufficiency. Horm Res, 1998;50:147-150 28 https://www.halesmeds.com/monographs/61420?q=somatro, accessed 1/30/2020


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Females and Males of Reproductive Potential Nonclinical Experience29 No adverse fertility effects were observed in male or female rats administered subcutaneous somapacitan at doses producing exposures at least 29 times above the expected maximum clinical exposure at 8 mg/week. Clinical Experience Sogroya (somapacitan-xxxx) injection, for subcutaneous use has only been used in the applicant’s clinical trials and is not currently approved in any country. The applicant provided a summary of use of somapacitan and fertility in their BLA submission and reports that no infertility cases were found. There is no published information on the use of Sogroya (somapacitan-xxxx) and fertility effects. Growth Hormone Deficiency - Female Fertility Published animal studies support the existence of multiple mechanisms by which growth hormone (GH) modulates reproductive function. In vitro studies suggest that GH is involved in ovarian steroidogenesis, folliculogenesis, ovulation, oocyte quality and competence, and implantation through modulation of endometrial receptivity.30 The absence or low levels of GH and insulin-like growth factor-1 (IGF-1) have clinical effects on the reproductive system in women. Girls with GHD have delayed pubertal development and in adulthood present with a condition of subfertility. Women with GHD often require assistive reproductive technologies to achieve a pregnancy.31 In addition, somatropin has been used off-label as an adjunct in ovulation induction and IVF in women without GHD for over 25 years to improve the ovulation rate, reduce the duration of ovarian stimulation required for oocyte retrieval, and collect a greater number of oocytes in a cycle. However, there are no data showing evidence that the use of rhGH (somatropin) with ovulation induction and IVF increases the chances of a live birth.32,33 Growth Hormone Deficiency - Male Fertility GH is important in the timing of puberty and gonadal size and acts indirectly via hepatic insulin-like growth factor-1 (IGF-1), at the testicular level to promote sperm production. Men with GHD have small testes and low to no sperm count. In animal studies, administration of GH to GH-deficient rats improved sperm concentration, motility, and morphology. Sparse data is available on improved spermatogenesis in men treated receiving rhGH (somatropin); however,

29 Refer to the final Nonclinical Review, 4/17/2020 30 Albu D, Albu A. Is growth hormone administration essential for in vitro fertilization treatment of female patients with growth hormone deficiency. Syst Biol in Reprod Med, 2019; 65(1): 71-74 31 Giampietro A, Milardi D. The effect of treatment with growth hormone on fertility outcome in eugonadal women with growth hormone deficiency: report of four cases and review of the literature. Fertility and Sterility, 2009; 91(3):7-11 32 ibid 33 Hart RJ, Rombauts L, Norman RJ. Growth hormone in IVF cycles: any hope? Curr Opin Obstet Gynecol, 2017; 29(3):119-125


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some men showed no improvement in sperm count. Larger studies are needed to determine the effects of rhGH (somatropin) on male spermatogenesis and fertility.34,35,36 DISCUSSION AND CONCLUSIONS Pregnancy Growth hormone deficiency (GHD) is a rare disorder with onset occurring either in childhood typically genetic or idiopathic causes) or adulthood (typically acquired cause). There has been no reported use of Sogroya (somapacitan-xxxx) injection in pregnant women. However, there are published studies detailing several decades of clinical use of short-acting, recombinant human growth hormone (somatropin) during pregnancy in women with (GHD) that did not identify any signal for adverse maternal or pregnancy outcomes. The difference between somapacitan (long-acting rhGH) and somatropin (short-acting rhGH) is a single substitution in the amino acid backbone to which an albumin binding moiety is attached which allows reversible binding to endogenous albumin to delay elimination of somapacitan and prolong the in vivo half-life and duration of action.37 Somapacitan was not teratogenic in rats and rabbits when administered subcutaneously during organogenesis at doses approximately 12-times the clinical exposure at the maximum recommended human dose (MRHD) of 8 mg/week. No adverse developmental outcomes were observed in offspring of rats administered somapacitan during organogenesis through lactation at approximately 275 times the clinical exposure at the MRHD. Several publications have called into question whether GH replacement therapy during pregnancy in women with GHD is needed as the placenta produces and secretes a GH variant called placental growth hormone (PGH) with levels increasing throughout pregnancy, peaking at approximately 35 to 36 weeks gestation. PGH is reported to have a high affinity for GH receptors, gradually replacing pituitary GH and controlling production of maternal insulin-like growth factore-1 (IGF-1).38 Available published studies have not shown any difference in pregnancy outcomes with no use of growth hormone replacement therapy, use of growth hormone replacement therapy during the 1st and 2nd trimester, or use of growth hormone replacement therapy throughout pregnancy in women with GHD. DPMH concludes that published data with short-acting recombinant human growth hormone (rhGH, somatropin) over several decades of use in pregnant women are useful in evaluating the safety of Sogroya (somapacitan-xxxx) in pregnant women; therefore, DPMH does not recommend that a postmarketing pregnancy safety study be required at this time for Sogroya (somapacitan-xxxx). Furthermore, no adverse developmental outcomes have been described in

34 Khourdaji I, Lee H, Smith R. Frontiers in hormone therapy for male fertility. Translational Andrology and Urology, 2019; 7(Supple 3):S353-S366 35 Magon N, Singh S, Sahay R. Growth hormone in male fertility. Ind J Endocrinol Metabol, 2011; 15(Suppl3):S248-S-249 36 Bartke A. Effects of growth hormone on male reproductive functions. J of Andrology, 2000;21(2):181-188 37 Refer to applicant proposed labeling, 8/28/2019 38 Vila G, Akerblad AC, et al. Pregnancy outcomes in women with growth hormone deficiency. Fertility and Sterility, 2015; 104(5):1210-1217


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animal reproduction studies for either short-acting or long-acting rhGH. However, whether continuation of GH replacement therapy is necessary during pregnancy remains an unanswered question. At a minimum, pregnant women should not be excluded from clinical trials for rhGH products and their outcomes should be monitored. Labeling subsection 8.1 Pregnancy should convey that there is no pregnancy outcome information with the use of Sogroya in pregnant women; however, no safety concerns or adverse pregnancy outcomes have been reported with several decades of rhGH use in pregnant women. Lactation There are no data on the presence of somapacitan in human milk; however, limited published data with short-acting rhGH along with the pharmacological properties of somapacitan, including its long peptide chain and large molecular weight (23305.10 g/mol, of which the albumin binding moiety is 1191.39 g/mol),39 indicate the unlikelihood of any significant drug transfer into milk or oral absorption by a breastfed infant. For reference, the molecular weight of short-acting rhGH is ~ 22100 g/mol.40 However, animal data did show the presence of somapacitan in rat milk at up to 50% of plasma levels (of note, animal milk levels were not measured with current approved short-acting rhGH products; therefore, it is not possible to compare animal milk levels with different rhGH products). When a drug is present in animal milk it is expected to be present in human milk; however, the concentration of a drug in animal milk is not predictive of the amount found in human milk. No adverse developmental outcomes were reported in pups in the pre- and post-natal study with maternal somapacitan doses that produced exposures greater than 600 times the expected maximum clinical exposure. Several studies investigating the potential use of rhGH as a galactagogue showed an increase in milk production in both normal lactating women and women with lactation insufficiency; however, larger studies would be needed to support such a claim.41 One study demonstrated that administration of short-acting rhGH to 8 women for 7 days did not increase the normal breastmilk concentration of human growth hormone.42 In addition, no adverse effects were reported in 34 breastfed infants with maternal administration of short-term rhGH for 7 days.43,44,45

39 Refer to applicant proposed labeling, 8/28/2019 40 https://www.drugbank.ca/drugs/DB00052 41https://www micromedexsolutions.com/micromedex2/librarian/CS/86930C/ND_PR/evidencexpert/ND_P/evidencexpert/DUPLICATIONSHIELDSYNC/E58275/ND_PG/evidencexpert/ND_B/evidencexpert/ND_AppProduct/evidencexpert/ND_T/evidencexpert/PFActionId/evidencexpert.IntermediateToDocumentLink?docId=3635&contentSetId, =35&title=GROWTH HORMONE&servicesTitle=GROWTH HORMONE&navResults=clinicalRefTox, accessed 1/30/2020 42 Milsom SR, Breier BH, et al. Growth hormone stimulates galactopoiesis in healthy lactating women. Acta Endocrinol, 1992; 127:337-343 43 ibid 44 Mislom SR, Rabone DL, et al. Potential role for growth hormone in human lactation insufficiency. Horm Res, 1998; 50:147-150 45 Gunn AJ, Gunn TR, et al. Growth hormone increases breastmilk volumes in mothers of preterm infants. Pediatrics; 1996; 98(2 pt1):279-282


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DPMH concludes that the lactation data with maternal use of short-acting rhGH for 7 days, along with the pharmacological properties of rhGH, are sufficient to inform the use of Sogroya during lactation; and therefore, a requirement for a postmarketing lactation study Sogroya (somapacitan-xxxx) is not recommended at this time. Labeling subsection 8.2 Lactation should include the limited published lactation data with short-acting rhGH, a statement regarding the presence of drug in animal milk, and the required PLLR lactation benefit/risk statement. It is not necessary or meaninful to inlcude the concentration of drug in animal milk as the concentration of a drug in animal milk is not prdictive of the concentration in human milk. Females and Males of Reproductive Potential There are no pregnancy testing or contraception recommendations or requirements with the use of Sogroya (somapacitan-xxxx) in females and males of reproduction potential. There are no adverse effects on fertility reported in humans or from animal studies. Furthermore, recombinant human growth hormone (rhGH, somatropin) has been used off-label as an adjunct in ovulation induction and IVF in women without growth hormone deficiency (GHD) for over 25 years to improve the ovulation rate, reduce the duration of ovarian stimulation required for oocyte retrieval, and collect a greater number of oocytes in a cycle and in males with GHD in an attempt to increase sperm count and fertility. Subsection 8.3 Females and Males of Reproductive Potential omitted from Sogroya labeling as there is no information to convey regarding pregnancy testing, contraception use, or adverse fertility effects in females or males of reproductive potential. LABELING RECOMMENDATIONS DPMH revised subsections 8.1 and 8.2 of labeling for compliance with the PLLR (see below) and has incorporated the animal data description recommendations by the Nonclinical Reviewers in subsection 8.1. In addition, the Office of Regulatory Policy (ORP), in an email dated February 24, 2020,46 concurred with our suggested approach for the inclusion of clinical rhGH product class information in subsections 8.1 and 8.2. DPMH refers to the final BLA action for final labeling.

46 “ORP does not have any comments on the language and approach you propose below, provided that you are relying on non-product specific literature or Sogroya-specific information to comply with PLLR. This would be consistent with the policy and approach ORP/OCC are recommending for compliance with the PLLR. “, Email from Nita Shah, 2/24/2020.


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DPMH Proposed Pregnancy and Lactation Labeling FULL PRESCRIBING INFORMATION 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on SOGROYA use in pregnant women; however, published studies with short-acting recombinant human growth hormone (rhGH) use in pregnant women over several decades have not identified any drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, somapacitan was not teratogenic in rats and rabbits

. No adverse developmental outcomes were observed in

organogenesis through lactation at approximately 275 times the clinical exposure at the MRHD (see Data). The estimated background risk of birth defects and miscarriage for the indicated population is unknown.

. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In an embryo-fetal development study in rats, somapacitan was administered via subcutaneous injection at doses of 2, 6, 18 mg/kg/day during the period of organogenesis from gestation Day 6 to 17. Fetal viability and development were not affected at doses up to 6 mg/kg/day (31-times the

MRHD). Transient, fetal skeletal variations (short/bent/thickened long bones) were observed at 18 mg/kg/day (261-times the MRHD). In an embryo-fetal development study in rabbits, somapacitan was administered via subcutaneous injection at doses of 1, 3, 9 mg/kg every two days during the period of organogenesis from gestation Day 6 to 18. Fetal viability and development were not adversely affected at doses of 1 mg/kg every two days (12-times the MRHD, based on AUC). Reduced fetal growth was observed at doses >3 mg/kg every two days (≥130-times the

MRHD, based on C12h). In a pre- and post-natal study in pregnant rats, somapacitan was administered via subcutaneous injection at doses of 4, 9, 18 mg/kg twice a week from gestation Day 6 to lactation Day 18. No adverse developmental effects were observed in offspring at doses up to 9 mg/kg (275-times the MRHD). Increased incidence of renal pelvic dilatation was observed on postnatal day 21 at 18 mg/kg twice weekly (630-times the MRHD) but was not observed in the adult F1 generation.


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8.2 Lactation Risk Summary There is no information on the presence of somapacitan in human milk, the effects on the breastfed infant, or the effects on milk production. In an animal pre- and post-natal study, somapacitan related material was secreted into rat milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Available published data describing administration of short-acting recombinant human growth hormone (rhGH) to lactating women for 7 days reported that short-acting rhGH did not increase normal breastmilk concentrations of growth hormone and no adverse effects were reported in breastfed infants.The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SOGROYA and any potential adverse effects on the breastfed infant from SOGROYA or from the underlying maternal condition.


--------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically. Following this are manifestations of any and allelectronic signatures for this electronic record.--------------------------------------------------------------------------------------------/s/------------------------------------------------------------

JEANINE A BEST04/17/2020 02:35:00 PM

TAMARA N JOHNSON04/17/2020 03:00:18 PM

LYNNE P YAO04/21/2020 03:45:51 PM



Clinical Inspection Summary BLA 761156 somapactitan

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Clinical Inspection Summary

Date 4/3/2020

From

Cynthia F. Kleppinger, M.D., Senior Medical OfficerMin Lu, M.D., M.P.H., Team LeaderKassa Ayalew, M.D., M.P.H., Branch ChiefGood Clinical Practice Assessment Branch (GCPAB)Division of Clinical Compliance Evaluation (DCCE)Office of Scientific Investigations (OSI)

To

Geanina Roman-Popoveniuc, M.D., Clinical ReviewerMarina Zemskova, M.D., Clinical Team LeaderLinda V. Galgay, RN, MSN, Senior Regulatory Project ManagerDivision of Metabolism and Endocrinology Products (DMEP)

BLA 761156Applicant Novo Nordisk IncDrug Somapactitan NME YesTherapeutic Classification Growth hormone derivative

Proposed Indication Replacement of endogenous growth hormone in adults with growth hormone deficiency

Consultation Request Date 11/1/2019Summary Goal Date 4/28/2020Action Goal Date 8/28/2020PDUFA Date 8/28/2020

I. OVERALL ASSESSMENT OF FINDINGS AND RECOMMENDATIONS

The inspection for this biologics license application (BLA) consisted of two domestic and two foreign clinical sites.

In general, based on the inspections of the four clinical sites, the inspectional findings support validity of data as reported by the sponsor under this BLA.



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II. BACKGROUND

Novo Nordisk has submitted an original biologics license application (BLA) for somapacitan injection, a long-acting growth hormone derivative, for replacement of endogenous growth hormone (GH) in adults with growth hormone deficiency (AGHD). Novo Nordisk is filing for approval of this product as a 10 mg/1.5 mL prefilled multi-dose pen.

Inspections were requested for Study NN8640-4054 (REAL 1) “A Multicenter, Multinational, Randomized, Parallel-Group, Placebo-Controlled (Double Blind) and Active-Controlled (Open) Trial to Compare the Efficacy and Safety of Once-Weekly Dosing of Somapacitan (NNC0195-0092) With Once-Weekly Dosing of Placebo and Daily Norditropin® FlexPro® in Adults With Growth Hormone Deficiency for 35 Weeks, Followed by a 53-Week Open-Label Extension Period”. Norditropin® is the registered trademark for Novo Nordisk’s recombinant human GH product, somatropin. Norditropin® FlexPro® is the prefilled pen with liquid hGH to be used as comparator. Norditropin® FlexPro® is currently approved worldwide for Adult Growth Hormone Deficiency (AGHD) and for GHD, Turner syndrome, Short for Gestational Age (SGA) and in EU for growth retardation in prepubertal children due to chronic renal disease.

This was a multicenter, multinational, randomized, parallel-group, placebo-controlled (doubleblind) and active-controlled (open) trial. The trial compared the efficacy and safety of once weeklydosing of somapacitan with once-weekly dosing of placebo and daily dosing of Norditropin® FlexPro® in AGHD subjects during a 34 +1 week period (8 week dose titration, 26 week fixed dose treatment followed by 1 week washout), with a 52+1 week extension period (8 week dose titration, 44 week fixed dose treatment followed by 1 week washout). Total duration of treatment was 86 weeks.

The primary endpoint was change from baseline to end of main trial period (Week 34) in truncalfat percentage.

Body composition was measured by DXA (Dual energy X-ray Absorptiometry) and truncal fatpercentage was defined as 100 times truncal fat mass (kg) divided by the sum of truncal fat mass(kg) and truncal lean body mass (kg).

Three DXA scans were performed: 1) at screening (or within 4 days after the screening), 2) atthe end of the main trial period and 3) at the end of the extension period. A limited number ofrepeat scans could be done if required due to technical reasons. If a subject withdrew from thetrial, an end-of trial DXA was performed.

After the main trial period, placebo subjects were re-randomized 1:1 to somapacitan orNorditropin® FlexPro® within the same strata as used for the first randomization. During theextension period subjects were seen on a regular basis for adverse events, safety laboratorymeasurements, and efficacy.

Following DXA scan acquisition, each trial site was responsible for transferring each DXA scanto the imaging laboratory for quality review and analysis. DXA analysis data was transferred



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from the imaging laboratory to Novo Nordisk immediately prior to the database locks of themain and extension periods. To avoid un-blinding, the investigators received the results from theanalysis after last subject last visit of the extension period.

The trial began October 31, 2014 and completion of the main trial occurred May 01, 2017.Database lock for the main trial occurred June 23, 2017. Cut-off for inclusion of importantprotocol deviations was July 26, 2017. The trial completed May 07, 2018. Final database lockwas June 25, 2018.

There were 92 sites in 16 countries that randomized subjects. There were 301 subjects randomized and 300 subjects received trial drug. A total of 277 subjects completed treatment; 272 subjects went into the extension period; 255 subjects completed the extension period.

III. RESULTS (by Site)

NOTE: Site inspections focused on review of informed consent documents (ICDs), institutional review board (IRB)/ ethics committee (EC) correspondences, 1572s/investigator agreements, financial disclosures, training records, CVs and licenses, delegation of duties, monitoring logs and reports, inclusion/exclusion criteria, enrollment logs, subject source documents including medical history records, drug accountability, concomitant medication records, and adverse event reports. Source records were compared to the sponsor’s data line listings.

1. Corin Virgil Badiu, M.D., Ph.D.Institutul National de Endocrinologie C.I. ParhonBd. Aviatorilor Nr. 34-36Bucuresti, Sector 1 11863RomaniaSite: 455

Dates of inspection: January 27 – 31, 2020

There were 22 subjects screened and 16 subjects enrolled into the study; 10 subjects completed the study. There were 16 subject records reviewed.

The institutional review board of record was . This was a non-

IND site.

Two sponsor representatives (the local clinical trial manager and a research associate) were present to help translate.

Dr. Badiu is a professor of endocrinology at C.I. Parhon National Institute of Endocrinology. The institute is a government-run hospital that serves all of Romania for


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endocrine disorders. Dr. Badiu has worked there since 1991. . The site did not advertise.

Source records were organized, legible, and in good condition. Original diaries were all present at the trial site in subject binders. Data was transmitted from the site to the sponsor via electronic case report forms (eCRFs). All audit trails were saved and available for review. At the close of the trial, all electronic data was placed on a CD and shipped from the sponsor to the site.

The site and study monitor documented protocol deviations and associated reports, which were kept in regulatory binders. Subjec , Visit 10, took the investigational product (IP) early, resulting in possible interference with laboratory samples. This was documented and reported as a protocol deviation.

There was no accidental unblinding. DXA scans were not received at this site; only confirmations were received with signatures of review by the site investigator.

Source records were compared to the sponsor data line listings. There were no discrepancies. There was no under-reporting of adverse events. The primary efficacy endpoint was verifiable.

The inspection revealed adequate adherence to the regulations and the investigational plan. There were no objectionable conditions noted and no Form FDA-483, Inspectional Observations, issued.

2. Hiroshi Nishioka, M.D., Ph.D.Toranomon HospitalDivision of Endocrinology#2-2-2 Toranomon Minatu-kuTokyo 105-8470JapanSite: 204


There were 10 subjects screened and 8 subjects enrolled into the study; 8 subjects completed the study. There were 8 subject records reviewed.

The institutional review board of record was the .

Independent translators were hired by the sponsor for this inspection. Dr. Nishioka and most of the staff interviewed did not speak English; most of the records were in Japanese as well. The two translators were present throughout the inspection and provided translations


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of all conversations and documents. Two staff from the Japan Pharmaceuticals and Medical Devices Agency (PMDA) were present as observers.

Dr. Nishioka is presently chief of the endocrinology department. He has been conducting clinical studies for more than a decade. Dr. Nishioka accepted the role of principal investigator for Study NN8640-4054 around March 2018 after the retirement of the original principal investigator Dr. Shozo Yamada.

Each subject’s records consisted of a study notebook and source documents that documented study endpoints. The subject diaries for at least 6 subjects that were used for reporting dosing schedules by the subject had the date “prefilled” by the Clinical Research Coordinator (CRC). This deviation was reported by the sponsor’s monitors and reported to the IRB as a significant protocol deviation.

The site was blinded to the treatment and on-going laboratories/scans that could reveal the study arm for each subject. Laboratory specimens and DXA scans were obtained on site and sent directly to third party reviewers without disclosing results to the site.

Source records were compared to the sponsor data line listings. There were no discrepancies. There was no under-reporting of adverse events. The primary efficacy endpoint was verifiable.


3. Larry D. Stonesifer, M.D.34509 9th Avenue South, Suite 200Federal Way, WA 98003Site: 111


There were 19 subjects screened and 4 subjects enrolled into the study; 3 subjects completed the study (one subject completed the main part of study but not the extension). There were 4 subject records reviewed.

The institutional review board of record was IRB.

Dr. Stonesifer has been in private practice since 1984. Dr. Stonesifer’s private clinic and clinical research clinic occupy different suites in the same building since 1989. Clinical research occupies approximately 30% of his time. The subjects enrolled in the study are patients seen in his private practice. Dr. Stonesifer plans to close his clinic practice at the end of 2021.


(b) (4)


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All source documents were paper based. Designated staff entered the data required bythe protocol into the electronic case report forms (eCRFs). All audit trails were saved and available for review. After study closeout, the sponsor provided the site a flash drive with the subject eCRFs.

Source records were compared to the sponsor data line listings. There were minor discrepancies noted for time of dosage between the patient daily diary and eCRF. The time of Norditropin® FlexPro® dosing was incorrectly converted from source standard time to military time in the eCRF.

For Subject , during the main trial period Week 13, no “am” or “pm” is checked on the patient diary for time of Norditropin® FlexPro® dose. The time is entered as “pm” in the eCRF.

There was no under-reporting of adverse events. The primary efficacy endpoint was verifiable.

It was reported in the Clinical Study Report that the DXA reports for 4 patients (at Visit 2) were by mistake temporarily filed within the subject files, which could potentially unblind the investigator/site. This was investigated during the inspection. DXA scan reports were generated electronically and auto faxed by imaging facility to the site during the study. Dr. Stonesifer had a Service Agreement with the imaging facility. There was no unblinding agreement in place.


(b) (6)

(b) (6)

(b) (4)

(b) (4)

(b) (4)

(b) (6)


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The DXA images were submitted to through a secure internet website. The original DXA reports were filed in the subject binders for the following four subjects:

. When the reports were discovered in the subject records by the monitor on 4/3/17, the monitor instructed the site staff to remove the reports from the subject binders. During the monitor’s tour of the DEXA facility, the monitor was to ensure that the subject scans were stored appropriately (i.e.; access to the unanalyzedsubject scans during and after the end of trial) at the radiology unit and not within the subject source binder. The documentation of instruction to stop sending DXA scans to the investigator site is not present; however, the monitoring visit report for visit of the DEXA facility states that the scans were appropriately stored.

During the inspection, it was confirmed that the DXA scan reports were removed from the study files of the 4 enrolled subjects. However, the DXA reports for screen-failed Subjects

were present in the subject charts. On 12/20/2018, after study closure, the results (un-blinded) from DXA scans was provided to the site by the sponsor.

It was confirmed that the investigator and site staff were re-trained regarding blinding requirements for DXA scans. Training for image quality and transfer was provided also to the imaging facility radiologist.


4. Michelle D. Welch, M.D.Consano Clinical Research4118 Pond Hill, Bld #3Shavano Park, TX 78231Site: 126

Dates of inspection: February 10 – 14, 2020

There were 24 subjects screened and 13 subjects enrolled into the study; 7 subjects completed the study (one subject lost to follow-up, one subject withdrew due to elevated liver enzymes, one subject withdrew due to lack of efficacy, and three withdrew consent for personal reasons). There were 13 subject records reviewed.

The institutional review board of record was IRB.

Dr. Welch is the founder of Diabetes and Metabolism Specialists, San Antonio in San Antonio, Texas and has about 10 years of clinical research experience. The study was initiated at the firm’s previous address before the firm moved to Shavano Park. Dr. Welch’s private practice is in the same building as the research site. Most of the subjects in the study came from Dr. Welch’s private practice and a few were referred by colleagues.


(b) (4)

(b) (6)

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(b) (4)

(b) (6)


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There was no advertisement.

Source records were legible, organized and available. The eCRFs had visible audit trails showing queries and changes to entry values, including the date/time and person responsible for the change. Source records were compared to the sponsor data line listings. There were no discrepancies. There was no under-reporting of adverse events. The primary efficacy endpoint was verifiable.


{See appended electronic signature page}

Cynthia F. Kleppinger, M.D.Senior Medical OfficerGood Clinical Practice Assessment BranchDivision of Clinical Compliance EvaluationOffice of Scientific Investigations

CONCURRENCE: {See appended electronic signature page}

Min Lu, M.D., M.P.H.Team LeaderGood Clinical Practice Assessment BranchDivision of Clinical Compliance EvaluationOffice of Scientific Investigations

CONCURRENCE: {See appended electronic signature page}

Kassa Ayalew, M.D., M.P.HBranch ChiefGood Clinical Practice Assessment Branch Division of Clinical Compliance EvaluationOffice of Scientific Investigations



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cc:

Central Doc. Rm./ BLA 761156DMEP/Acting Division Director/ Lisa YanoffDMEP /Acting Deputy Director/William ChongDMEP/Team Lead/Marina ZemskovaDMEP/Clinical Reviewer/ Geanina Roman-PopoveniucDMEP /Regulatory Project Manager/Linda V. GalgayOSI/DCCE/Division Director/Ni Aye KhinOSI/DCCE/GCPAB/Branch Chief/Kassa AyalewOSI/DCCE/GCPAB/Team Leader/Min LuOSI/DCCE/GCPAB Reviewer/Cynthia KleppingerOSI/DCCE/GCPAB/Program Analyst/Yolanda PatagueOSI/DCCE/Database Project Manager/Dana Walters



CYNTHIA F KLEPPINGER04/03/2020 04:22:36 PM

MIN LU04/03/2020 05:18:15 PM

KASSA AYALEW04/03/2020 05:22:06 PM



1

LABEL AND LABELING REVIEWDivision of Medication Error Prevention and Analysis (DMEPA)

Office of Medication Error Prevention and Risk Management (OMEPRM)Office of Surveillance and Epidemiology (OSE)

Center for Drug Evaluation and Research (CDER)

*** This document contains proprietary information that cannot be released to the public***

Date of This Review: February 11, 2020

Requesting Office or Division: Division of Metabolism and Endocrinology Products (DMEP)

Application Type and Number: BLA 761156

Product Name and Strength: Sogroya (somapacitan-xxxxa) injection, 10 mg/1.5 mL (6.7 mg/mL)

Product Type: Combination Product (Drug-Device)

Rx or OTC: Prescription (Rx)

Applicant/Sponsor Name: Novo Nordisk, Inc.

FDA Received Date: August 28, 2019

OSE RCM #: 2019-1822

DMEPA Safety Evaluator: Melina Fanari, R.Ph.

DMEPA Team Leader: Sevan Kolejian, PharmD, MBA

a Sogroya is a biologic. The proper name consisting of a core name (somapacitan) and an FDA-designated suffix is not available at this time. Since the proper name for Sogroya has not yet been determined, “somapacitan-xxxx” is used throughout this review as the proper name for this product.


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1 REASON FOR REVIEWAs part of the approval process for Sogroya (somapacitan-xxxxa) injection, the Division of Metabolism and Endocrinology Products (DMEP) requested that we review the proposed Sogroya prescribing information (PI), prescribing patient information (PPI), instruction for use (IFU), container labels, and carton labeling for areas of vulnerability that may lead to medication errors.

1.1 REGULATORY HISTORYDMEPA previously reviewed the Human Factors Engineering Plan and Type C Meeting request for the Agency’s Written Responses on the Human Factors analysis and strategy to bridge the Sogroya pen-injector to the currently marketed Norditropin FlexProb. The Sogroya pen-injector shares the same device user interface, intended use, users, and use environment as the currently marketed Norditropin FlexPro. Based on this review DMEPA concluded that a human factors differentiation validation study was not needed and the approach to bridge the human factors data from the Norditropin Flexpro pen-injector was acceptable. In addition, the Division of Medical Policy Programs also provided recommendations for the IFU within their review dated August 20, 2018c and September 27, 2019d.

2 MATERIALS REVIEWED

Table 1. Materials Considered for this Label and Labeling ReviewMaterial Reviewed Appendix Section

(for Methods and Results)

Product Information/Prescribing Information A

Previous DMEPA Reviews B

ISMP Newsletters C-N/A

FDA Adverse Event Reporting System (FAERS)* D-N/A

Other E-N/A

Labels and Labeling G

N/A=not applicable for this review

b Hoste, S, Use Related Risk Analysis Review Somapacitan (IND 116327). FDA, CDER, OSE Silver Spring (MD): 2018 Aug 22. OSE RMC No.: 2018-1398c Dowdy, K. Patient Labeling Review for NNC0195-0092 (NN8640). Silver Spring (MD): FDA, CDER, OMP, OMPI, DMPP (US); 2018 AUG 20. IND 116327d Booker, N. Patient Labeling Review for Norditropin. Silver Spring (MD): FDA, CDER, OMP, OMPI, DMPP (US); 2019 September 27. NDA 021148


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Table 1. Materials Considered for this Label and Labeling ReviewMaterial Reviewed Appendix Section

(for Methods and Results)

*We do not typically search FAERS for our label and labeling reviews unless we are aware of medication errors through our routine postmarket safety surveillance

3 FINDINGS AND RECOMMENDATIONS

Tables 2 and 3 below includes the identified medication error issues with the submitted Prescribing Information (PI), Prescribing Patient Information (PPI), Instruction for Use (IFU), container labels, and carton labeling, our rationale for concern, and the proposed recommendation to minimize the risk for medication error. We note that the IFU for Sogroya is based on the IFU for the currently marketed Norditropin FlexPro and in alignment with recommendations from previous reviewsb,c,d .

Table 2. Identified Issues and Recommendations for Division of Metabolism and Endocrinology Products (DMEP)

IDENTIFIED ISSUE RATIONALE FOR CONCERN RECOMMENDATION

Prescribing Information – General Issues

1. Some instances of strength expression utilize a trailing zero.

Minimize risk of 10-fold dose misinterpretation.

Remove all instances where a trailing zero is utilized (e.g. 1 mg rather than 1.0 mg).

2. Use of symbol ‘+’ in highlights and 2.2.

Improve clarity. Consider removing the ‘+’ symbol since it is not necessary.

3. Strength presentation is based on total content of pen.

Entire contents of the pen are not delivered for every recommended dosage.

We defer to OPQ for determination of the appropriate strength presentation (6.7 mg/mL vs. 10 mg/1.5 mL). Ensure that the OPQ determined strength presentation is consistent throughout the label and labeling.


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Table 3. Identified Issues and Recommendations for Novo Nordisk, Inc. (entire table to be conveyed to Applicant)


ALL Carton Labeling and Container Labels

1. Proprietary name is absent from labeling.

Proper product identification.

Revise all labels and labeling to include the conditionally approved name ‘Sogroya’.

2. Package type term ‘Single patient use only’ is located on lower portion of principle display panel (PDP).

Increase prominence. Relocate the statement ‘Single patient use only’ to a more prominent area of the PDP such as after the product name and strength.

3. The expiration date is not defined.

Minimize risk for deteriorated drug medication errors.

We request that you define the expiration date. FDA recommends that the human-readable expiration date on the drug package label include a year, month, and non-zero day. FDA recommends that the expiration date appear in YYYY-MM-DD format if only numerical characters are used or in YYYY-MMM-DD if alphabetical characters are used to represent the month. If there are space limitations on the drug package, the human-readable text may include only a year and month, to be expressed as: YYYY-MM if only numerical characters are used or YYYY-MMM if alphabetical characters are used to represent the month. FDA recommends that a hyphen or a space be used to separate the portions of the expiration date.

All Carton Labeling


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1. Strength presentation lacks sufficient prominence, in particular compared to the net quantity statements.

Wrong strength medication errors could occur.

Consider the use of color, boxing or other means to increase the prominence of the strength presentation statement. In addition, consider relocating the net quantity statements away from the strength presentation statement.

2. Route of administration is not on the principle display panel.

Mitigate risk wrong route of administration errors.

Relocate the statement, ‘For subcutaneous administration only’, from the back panel to the principle display panel.

3. The “Usual Dose’ statement is missing.

Improve safe use of the product.

Add the following statement to the carton labeling:‘Recommended Dosage: See prescribing information.’

4. Manufacturer information (logo) on principle display panel competes in size and prominence with important information.

Distracts reader from important information.

Consider minimizing or removing manufacturer information (logo) from the principle display panel. We note the manufacturer information is also on the bottom panel.

6. Refrigeration statements requires revision.

Minimize potential for drug deterioration.

Revise the beginning of the refrigeration statement to read ‘Must be refrigerated…’.

7. The product identifier required under the drug supply chair security act (DSCSA) is missing.

DSCSA requires manufacturers and repackages, respectively, to affix or imprint a product identifier to each package and homogeneous case of a product intended to be introduced in a transaction

We recommend that you review the draft guidance to determine if the product identifier requirements apply to your product’s labeling.

The draft guidance is available from: https://www.fda.gov/uc


6


IDENTIFIED ISSUE RATIONALE FOR CONCERN RECOMMENDATIONin (to) commerce beginning November 27, 2017, and November 27, 2018, respectively.

m/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm621044.pdf

Instruction for Use

1. Bulleted items throughout IFU appear cluttered.

Improve readability. For improved readability a space should be included between each bulleted item.

2. Storage information Improve readability. Consider adding a chart (similar to that utilized in the prescribing information) to the response to the question: ‘How should I store my once weekly TRADENAME® Pen?’

4 CONCLUSION

Our evaluation of the proposed Sogroya Prescribing Information (PI), Prescribing Patient Information (PPI), Instruction for Use (IFU), container labels, and carton labeling identified areas of vulnerability that may lead to medication errors. Above, we have provided recommendations in Table 2 for the Division and Table 3 for the Applicant. We ask that the Division convey Table 3 in its entirety to Novo Nordisk, Inc. so that recommendations are implemented prior to approval of this BLA.


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APPENDICES: METHODS & RESULTS FOR EACH MATERIAL REVIEWED APPENDIX A. PRODUCT INFORMATION/PRESCRIBING INFORMATION

Error! Reference source not found. presents relevant product information for Sogroya received on August 28, 2019 from Novo Nordisk, Inc.

Product Name Sogroya

Initial Approval Date

N/A

Active Ingredient

somapacitan- xxxx

Indication o Adult: Replacement of endogenous GH in adults with growth hormone deficiency (AGHD)

Route of Administration

subcutaneous

Dosage Form Solution for injection

Strength 10 mg/1.5 mL

Dose and Frequency

o The proposed usual dosage in adult patients with adult GHD is mg/kg once weekly. Maximum weekly dose is 8 mg.

How Supplied Single count pre-filled pen-injector

Storage refrigerated at 2°C to 8°C (35.6°F to 46.4°F) and not frozen; when in use, this product can be stored for a maximum of 6 weeks at 2°C to 8°C (35.6°F to 46.4°F), including three days less than 30°C (less than 86°F).


(b) (4)

(b) (4)

(b) (4)

APPEARS THIS WAY ON ORIGINAL

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APPENDIX B. PREVIOUS DMEPA REVIEWS

On January 15, 2020, we searched for previous DMEPA reviews relevant to this current review using the terms, somapacitan. Our search identified 1 previous reviews b and we considered our previous recommendations to see if they are applicable for this current review.


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APPENDIX G. Label and LabelingG.1 List of Labels and Labeling Reviewed

Using the principles of human factors and Failure Mode and Effects Analysis,e along with postmarket medication error data, we reviewed the following Sogroya labels and labeling submitted by Novo Nordisk, Inc. on August 28, 2019.

Container label Carton Labeling Sample Container label Sample Carton Labeling Prescribing Information (Image not shown), available from Application 761156 -

Sequence 0001 - Draft PI Prescribing Patient Information (Image not shown), available from Application 761156

- Sequence 0001 - Draft PPI Instruction for Use (Image not shown), available from Application 761156 - Sequence

0001 - Draft IFU

G.2 Label and Labeling Images

Container Labels

e Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.


(b) (4)

1 Page(s) of Draft Labeling has been Withheld in Full as B4 (CCI/TS) immediately following this page


MELINA N FANARI02/11/2020 03:20:29 PM

SEVAN H KOLEJIAN02/11/2020 03:40:41 PM

